cancers Review Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer Antonio Lopez-Beltran 1,*,† , Alessia Cimadamore 2,† , Ana Blanca 3, Francesco Massari 4 , Nuno Vau 5, Marina Scarpelli 2, Liang Cheng 6 and Rodolfo Montironi 2,* 1 Unit of Anatomic Pathology, Department of Morphological Sciences, Cordoba University Medical School, 14004 Cordoba, Spain 2 Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, 60126 Ancona, Italy; [email protected] (A.C.); [email protected] (M.S.) 3 Maimonides Biomedical Research Institute of Cordoba, Department of Urology, University Hospital of Reina Sofia, 14004 Cordoba, Spain; [email protected] 4 Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; [email protected] 5 Medical Oncology, Champalimaud Clinical Center, 1400-038 Lisbon, Portugal; [email protected] 6 Department of Pathology and Laboratory Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; [email protected] * Correspondence: [email protected] or [email protected] (A.L.-B.); [email protected] (R.M.); Tel.: +34-9-5721-8992 (A.L.-B.); +39-0-71-596-4830 (R.M.); Fax: +34-9-5721-8229 (A.L.-B.) † These authors contributed equally to the work. Simple Summary: In this review, we examined relevant clinical trial results with immune check- point inhibitors in patients with metastatic urothelial cancer. We also focused on the potential of immunotherapy in the adjuvant and neoadjuvant setting or as part of drug combinations. Finally, we briefly review the current landscape of biomarkers of response to immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1) expression, tumor mutation burden, molecular subtypes Citation: Lopez-Beltran, A.; of bladder cancer, and immune-gene expression profiling. Cimadamore, A.; Blanca, A.; Massari, F.; Vau, N.; Scarpelli, M.; Abstract: A number of immune checkpoint inhibitors (ICIs) have been approved as first-line ther- Cheng, L.; Montironi, R. Immune apy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic Checkpoint Inhibitors for the Treatment of Bladder Cancer. Cancers urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs 2021, 13, 131. https://doi.org/ immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry cancers13010131 seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed Received: 10 November 2020 in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective Accepted: 30 December 2020 to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, Published: 3 January 2021 a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line Publisher’s Note: MDPI stays neu- treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab tral with regard to jurisdictional clai- and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for ms in published maps and institutio- cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with nal affiliations. chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial Copyright: © 2021 by the authors. Li- results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed censee MDPI, Basel, Switzerland. on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response This article is an open access article to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed. distributed under the terms and con- ditions of the Creative Commons At- Keywords: bladder cancer; variant histology; urothelium; PD-1; PD-L1; immunotherapy; tumor tribution (CC BY) license (https:// mutation burden; immune checkpoint inhibitor; biomarker; Durvalumab; Atezolizumab; Nivolumab; creativecommons.org/licenses/by/ Pembrolizumab; Avelumab 4.0/). Cancers 2021, 13, 131. https://doi.org/10.3390/cancers13010131 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 17 Keywords: bladder cancer; variant histology; urothelium; PD-1; PD-L1; immunotherapy; tumor Cancers 2021, 13, 131 mutation burden; immune checkpoint inhibitor; biomarker; Durvalumab; Atezolizumab;2 of 16 Nivolumab; Pembrolizumab; Avelumab 1. Introduction 1. IntroductionBladder cancer is considered one of the most aggressive neoplasms worldwide [1]. Nonetheless,Bladder cancer the majority is considered of patients one present of the mostwith the aggressive less aggressive neoplasms non-muscle worldwide invasive [1]. Nonetheless,bladder cancer; the majorityand about of 30% patients of patients present withpresent the with less aggressivemuscle invasive non-muscle disease, invasive which bladderportend cancer; a worse and prognosis about 30% due of patientsto its metastatic present withpotential. muscle The invasive all-stage disease, five-year which overall por- tendsurvival a worse (OS) prognosis rate for urothelial due to its carcinom metastatica potential.remains about The all-stage80%. Typically, five-year advanced overall survivaldisease (OS)or relapse rate for after urothelial radical carcinoma cystectomy remains correlate about with 80%. the Typically, poor advancedoutcomes dis-that easeaccompany or relapse these after radicalpatients. cystectomy Traditionally, correlate first-line with the therapy poor outcomes of metastatic that accompany urothelial thesecarcinoma patients. (mUC) Traditionally, remained first-lineunchanged therapy over th ofe metastaticlast decades urothelial and was carcinoma based on cisplatin (mUC) remainedcombinations unchanged as the overinitial the choice last decades [2–4]. Unfort and wasunately, based nearly on cisplatin all patients combinations will ultimately as the initialprogress choice and [2 –die4]. Unfortunately,from bladder nearly cancer all despit patientse the will initial ultimately response progress associated and die fromwith bladdercisplatin-based cancer despite combinations. the initial response associated with cisplatin-based combinations. ImmuneImmune checkpoint checkpoint inhibitors inhibitors have have become become an an increasingly increasingly used used therapeutic therapeutic option option inin many many solid solid tumors tumors [ 5[5–10].–10]. In In bladder bladder cancer, cancer, high high levels levels of of programmed programmed death-ligand death-ligand 11 (PD-L1) (PD-L1) expression expression (Figure (Figure1 )1) have have been been reported reported to to be be associated associated with with advanced advanced and and aggressiveaggressive tumors tumors with with poor poor survival survival outcomes outcomes [ 11[11,12].,12]. FigureFigure 1. 1.Programmed Programmed death-ligand death-ligand 1 (PD-L1)1 (PD-L1) membranous membranous immunostaining immunostaining in high-grade in high-grade urothelial urothelial carcinoma (22C3 antibody) (200×). carcinoma (22C3 antibody) (200×). PD-L1PD-L1 expression expression by by immunohistochemistry immunohistochemistry seems seems to beto be associated associated with with resistance resistance to intravesicalto intravesical bacillus bacillus Calmette-Guerin Calmette-Guerin (BCG) therapy(BCG) [therapy12]. Immune [12]. checkpointImmune checkpoint inhibitors (ICI)inhibitors have demonstrated (ICI) have demonstrated a higher benefit a higher in heavy benefit CD8 in immuneheavy CD8 cell i infiltratedmmune cell tumors infiltrated and intumors tumors and with in hightumors tumor with mutational high tumor burden mutational (TMB), burden such as (TMB), the case such of bladder as the cancer.case of Thebladder mechanism cancer. is The related mechanism to a greater is related T cell-mediated to a greater antitumor T cell-mediated immune antitumor response immune elicited byresponse the greater elicited availability by the greater of neoantigens, availability which of neoantigens, are able to improve which theare antitumorable to improve immune the responseantitumor [13 immune–15]. response [13–15]. AtezolizumabAtezolizumab was was the the first first PD-L1 PD-L1 inhibitor inhibitor that that received received accelerated accelerated approval approval by by the the FoodFood andand DrugDrug AdministrationAdministration (FDA)(FDA) in May 2016 because of the the results results derived derived from from a a phase 2 trial that demonstrated improved response rates compared to controls [16–18]. Thereafter, Nivolumab, Pembrolizumab, Avelumab, and Durvalumab have all shown therapeutic activity in mUC, and, therefore, they have received the FDA approval through different clinical trials reporting important differences in the response to ICI as compared Cancers 2021, 13, 131 3 of 16 with chemotherapy [19–25]. However, while Pembrolizumb showed an improved median survival from 7.4 months to 10.3 months (hazard ratio (HR) = 0.73, 95% CI 0.59–0.91; p = 0.002) compared to chemotherapy,